Abstract Postpartum depression (PPD), a subtype of MDD, has significant morbidity and mortality for mother and child, but current options for prevention, diagnosis and treatment are limited. An emerging area of research in mental health is the study of the gut microbiota. The microbiota-gut-brain axis in relation to PPD is a novel area of research. Animal research suggests specific groups of pro-inflammatory bacteria are associated with anxious and depressive behaviors while specific groups of anti-inflammatory bacteria are associated with decreased anxious and depressive behaviors. Animal studies also indicate that microbial variation is associated with changes in HPA stress reactivity and changes in serotonin (5-HT) metabolism. We propose translating these findings to a clinical study of perinatal women. We will use 16S rRNA sequencing to identify changes in microbial composition over the course of pregnancy in order to 1) determine if women who develop increased pro-inflammatory bacteria and decreased anti-inflammatory bacteria across pregnancy are more likely to develop PPD; 2) determine if perinatal alterations in gut microbiota affect postpartum stress reactivity; and 3) determine how perinatal alterations in gut microbiota associate with changes in 5-HT metabolism. This research will support my primary career goal to become an independently funded clinical scientist with the expertise necessary to conduct state-of-the-art mechanistic research of the microbiota-gut-brain axis and PPD. My long-term research objectives are to: 1) advance our understanding of the microbiota-gut-brain axis changes during perinatal period in relation to PPD; 2) continue to examine the mechanistic underpinnings of PPD with regards to increased stress reactivity and altered 5-HT system and neurotransmitter metabolism; 3) identify women at risk of developing PPD and to apply the knowledge gained from maternal studies to understand the impact of the maternal microbiota-gut-brain axis on the infant beginning in utero through the first year of life; and 4) translate what is learned to develop and advocate for individualized treatments for the mother-infant dyad utilizing the microbiota-gut-brain axis. The specific objectives to meet my career goal are to 1) become knowledgeable and adept in comparative metagenomics; 2) improve my capability to study component affective processes of PPD; 3) become skilled in assessing stress reactivity; 4) gain understanding of and to become dexterous at studying the 5-HT system and neurotransmitter metabolism; 5) obtain expertise in developing translational research that can integrate mechanistic findings from basic science to clinical research of perinatal populations and to generate pilot data that will be the foundation for future work. Future directions will include studying the joint effects of the perinatal microbiota changes and PPD on the infant microbiota, mother-infant interactions and infant cognitive outcomes in order to develop interventions to improve outcomes for mother and child. This career development application represents the critical next step in my academic and research training and to improved understanding of the microbiota-gut-brain axis and PPD.